tbuckley/cabot-search huggingface dataset:
Pitfalls with analyses of real-world data: A look at ASCO’s CancerLinQ Discovery Multiple Myeloma dataset.
Authors: Karen J Shou, Jennifer A Thornton, Kevin Sunderland, Christin DeStefano
Journal: Journal of Clinical Oncology (2023)

e20033 Background: Real world data (RWD) are increasingly used in oncology research. Yet, a big limitation of RWD is missing data, potentially generating misleading conclusions. Methods for handling missing data include excluding patients with missing variables, using machine-based or statistically-imputed values, or using proxies (surrogates). Another limitation deals with excluding deaths at time zero, which may lead to misleading conclusions when analyzing survival of patients with aggressive cancers. This work highlights the impacts data exclusion, variable surrogacy, and death at time zero have on survival analysis results. Methods: ASCO’s CancerLinQ Discovery Multiple Myeloma (MM) dataset was used to assess overall survival (OS) in patients with MM diagnosed from 2009-2021. Of the 34,234 patients included in the actual analyses, 3,582 (10%) were missing a recorded date of MM diagnosis. In these cases, dates of first anti-myeloma therapy were used as surrogates since most MMs are treated at diagnosis. OS was compared between MM patients with “known” vs. surrogate or “presumed” diagnosis dates. To assess how the inclusion of deaths at time zero may or may not affect OS, the data were first analyzed by excluding patients who died within 1 month of second primary malignancy (SPM) diagnosis, including secondary AML (sAML). A second analysis of the same sample added a constant (0.5) to all survival times, allowing for inclusion of patients who died within one month of diagnosis. Analyses were conducted with STATA Version 17.0 (College Station, TX). Results: Despite the strong, positive correlation between recorded MM diagnosis date and date of first anti-myeloma therapy, there was a statistically significant difference in survival of MM patients with a known vs. presumed date of diagnosis (median OS 115 vs. 45 months, HR 2.54, 95% CI 2.41-2.69, p &lt; 0.001). Dropping vs. including deaths within one month of diagnosis resulted in a marked difference (i.e., nearly 1 year) in median OS from the date of diagnosis of any SPM (113 vs. 103.5 months) as well as sAML (41 vs. 30.5 months). Conclusions: Although RWD hold promise, oncologists must be aware of common pitfalls in survival analyses: missing data, variable surrogates, and deaths at time zero being dropped. Patients with a recorded date of MM diagnosis appear to be fundamentally different from those who don’t have a date of diagnosis but do have a date of anti-myeloma therapy recorded. For aggressive malignancies, excluding patients who died at time zero can lead to over-estimation of survival. Adding a small constant (0.5) to the time variable can enable the inclusion of patients who die quickly after their cancer diagnosis. In conclusion, when utilizing RWD to guide clinical decision making, it is important to be aware of common threats to data validity, which can produce misleading results.
Association of alterations in multiple tumor suppressor genes with poor outcomes in patients with EGFR-mutant lung cancer.
Authors: Paul Stockhammer, Michael J Grant, Anna Wurtz, Giorgia Foggetti, Francisco Expósito, Jianlei Gu, Sangyun Chung, Fangyong Li, Zenta Walther, Scott N. Gettinger, Katerina A. Politi, Sarah B. Goldberg
Journal: Journal of Clinical Oncology (2023)

9104 Background: Co-occurring alterations in tumor suppressor genes (TSG) have been described as determinants of disease heterogeneity in EGFR-mutant non-small cell lung cancer (NSCLC), however, detailed analyses of their impact on patient outcomes are limited. Methods: Patients with EGFR-mutant NSCLC treated with EGFR tyrosine kinase inhibitors (TKIs) at the Yale Cancer Center who had tumor genomic profiling either before EGFR-TKI therapy (pre-TKI) or at disease progression (post-TKI) were included. Whole exome sequencing (WES) of paired pre- and post-TKI tumor specimens were performed for a subset of patients. The cohort was divided into three subgroups based on alterations in TP53 and five additional TSGs ( RB1, NF1, ARID1A, BRCA1 and PTEN): patients with tumors harboring a TP53 mutation plus a mutation in at least 1 additional TSG ( TP53 mut /TSG mut ), patients with tumors harboring a TP53 mutation without an additional TSG mutation ( TP53 mut /TSG wt ), and patients with TP53 wt tumors. Clinical characteristics including progression-free (PFS) and overall survival (OS) were assessed. Results: One-hundred-one patients were included in this retrospective study. TP53 mutations were identified in 65 (64%) tumors, of which 23 (35%) and 42 (65%) were classified as TP53 mut /TSG mut and TP53 mut /TSG wt , respectively. Among those cases with paired WES available (n = 34), frequencies of alterations in the six included TSGs did not significantly differ between pre- and post-TKI tumor specimens. In the full study cohort, the presence of a TP53 mutation was associated with numerically worse PFS (HR 1.46, CI 0.97 – 2.21, p = 0.09) and OS (HR 1.68, CI 1.05 – 2.70, p = 0.04) on first-line EGFR-TKI. Strikingly, after dividing the TP53 mut cohort into TP53 mut /TSG mut and TP53 mut /TSG wt cases, alterations in additional TSG were found to drive the poor outcomes: TP53 mut /TSG mut cases had significantly worse PFS and OS on first-line EGFR TKI than TP53 mut /TSG wt (mPFS 8.0 vs 10.6 months, p = 0.006; mOS 30.0 vs 33.3 months, p = 0.12) or TP53 wt cases (mPFS 8.0 vs 12.6 months, p &lt; 0.0001; mOS 30.0 vs 48.8 months, p = 0.001). There was no significant difference in PFS or OS between patients with TP53 mut /TSG wt and TP53 wt tumors. Similar outcome differences between the three groups were found in patients who received osimertinib in the second-line setting. Conclusions: The inferior outcomes associated with EGFR/TP53-mutant NSCLC tumors may be due to additional TSG alterations rather than TP53 mutational status alone. Alterations in the investigated TSGs did not appear to emerge under EGFR-TKI therapy, which suggests that they are truncal. Our findings may have implications for understanding the biologic underpinnings of differential outcomes to EGFR TKIs.
The current state and future of neoadjuvants in resectable melanoma: Review of phase II/III studies conducted between 2018-2022.
Authors: Chan Mi Lee, Matthew M Mirsky, Margaret Wang, Ankit Mangla
Journal: Journal of Clinical Oncology (2023)

e21568 Background: Adjuvant therapy with single agent anti-PD1 and BRAF/MEK-inhibitors (BRAF/MEKi) is approved for patients diagnosed with high-risk stage III melanoma. The goal of adjuvant therapy is to prevent the growth of the occult metastasis to distant organs. The premise of neoadjuvant therapy in clinical stage III melanoma is to allow for a better antigen exposure when checkpoint inhibitors are administered. We aimed to get an overview of the current state of neoadjuvant therapy in resectable melanoma. Methods: A systematic literature search was conducted in November 2022, using PubMed, American Society of Clinical Oncology (ASCO) Journal of Clinical Oncology and European Society for Medical Oncology (ESMO) abstract databases. Eligible studies included Phase 2 and 3 randomized controlled trials (RCT), single-arm trials, pooled analyses, and planned future trials published between 2018-2022 looking at the efficacy of neoadjuvants in resectable melanoma. Two individuals (CL and MM) screened all the studies, and 3 individuals (CM, MM, MW) went over the list of Abstracts. Primary outcomes and secondary outcomes, as well as median duration of follow up and Grade 3 or above adverse effects (AEs) were recorded. Abstracts with more recent findings or final publications were excluded in the final analysis. Results: A total of 14 published studies (4 RTCs, 5 single-arm, 2 OpACIN-neo and 3 related sub-analysis studies) and 16 abstracts (5 ESMO, 11 ASCO) were identified, representing 34 unique Neoadjuvant arms and a total of 1,496 patients. Thirteen of 27 trials making 71% of patients (n = 1061) tested immune checkpoint inhibitors (ICIs). Four of 27 trials of total n = 112 tested BRAF/MEKi. All ongoing or future studies (7 trials) tested combination of ICI with BRAF/MEKi or other molecules such as MDM2 inhibitors, interferon-α, or oncolytic viruses. Most of studies (54% of ICI studies, 50% of BRAF/MEK inhibitor trials, and 80% of other studies) used pathological response as their primary outcome. Other primary end points included event-free survival (EFS) and relapse-free survival (RFS), and 13/14 published studies and 13/16 abstracts met the primary end point. A pooled analysis of complete pathologic response (pCR) revealed an estimate of 38.3% ± 19.7 (mean ± SD) from 16 unique ICI neoadjuvant arms, 51.9% ± 5.3 for BRAF/MEKi (from 3 data points), and 21.0% ± 7.2 for other agents/combinations (from 3 data points). Rate of ≥ Grade 3 AEs was 28.7% ± 31.0 (from 11 data points) for studies testing ICI, 32.5% ± 14.1 (from 6 data points) for BRAF/MEKi, and 23.6% ± 20.2 (from 3 data points) from studies testing other agents/combinations. Conclusions: Recent studies have shown that neoadjuvant in resectable melanoma can offer increased therapeutic efficacy. While past studies have focused on PD-1 and CTLA-4 inhibitors, ongoing and future studies are beginning to test newer agents and novel molecular targets.
Effect of disease status prior to T-cell depleted allogeneic stem cell transplantation on relapse-free and overall survival in patients with adverse-risk acute myeloid leukemia (AML).
Authors: Alexandra Ewa Rojek, Mylove Mortel, Andrew S. Artz, Richard A. Larson, Hongtao Liu, Mariam Nawas, Olatoyosi Odenike, Wendy Stock, Michael Russell Bishop, Satyajit Kosuri
Journal: Journal of Clinical Oncology (2023)

7049 Background: Patients (pts) with adverse risk AML experience poor long term disease control. Some of these pts can be rescued with allogeneic stem cell transplantation (SCT). Adverse risk was defined by high risk cytogenetic and molecular markers (2017 European Leukemia Network criteria) and by disease status prior to SCT. We investigated outcomes of pts receiving in vivo T-cell depleted allogeneic SCT (TCD-SCT) at our center. Methods: We retrospectively analyzed 200 adverse-risk AML pts who received TCD-SCT from 2002-19. Pts were categorized into groups: untreated first relapse at SCT, primary induction failure with active disease at SCT, resistant to first induction but achieving morphologic complete remission (CR) by SCT, and induction sensitive CR with high-risk disease by ELN criteria. Outcomes were evaluated by 1-year (yr) and 3-yr relapse-free survival (RFS), overall survival (OS), and non-relapse mortality (NRM), and compared with log-rank tests of significance. Results: Baseline pt characteristics included a median age of 54 years (IQR, 44-61) with 62 (31%) pts older than 60, and 81 (41%) with HCT-CI score 3 or greater. All pts underwent in vivo TCD with alemtuzumab or ATG; 153 (77%) received reduced-intensity conditioning; 142 (71%) had 8/8 or 7/8 matched donors. Fourteen (7%) pts developed grade III-IV acute graft versus host disease (GVHD), and 25 (13%) developed chronic GVHD. With a median follow up of 14.3 months, cumulative incidence of relapse was 59% and NRM was 27%. Outcomes are summarized in the table. There was a statistically significant difference between categorized groups by RFS (p&lt;0.01) and OS (p&lt;0.01). Conclusions: We conclude that among adverse-risk AML pts, those in CR at time of TCD-SCT have superior survival outcomes to those with active disease. For those in CR at TCD-SCT, prior resistance to frontline induction was associated with inferior survival, suggesting that AML biology, treatment sensitivity, and remission status are important factors for TCD-SCT outcomes. The inferior outcomes observed for those with primary refractory disease suggest that while TCD-SCT can be effective with acceptable NRM, more work is needed to identify which pts can benefit from future transplant strategies. Better post-SCT therapy is needed to prevent relapses. [Table: see text]
Comparing the prognostic implications of spread through airspaces versus lymphovascular invasion in non-small cell lung cancer.
Authors: Rebecca Elizabeth Epstein, Nagashree Seetharamu, Michael J. Esposito
Journal: Journal of Clinical Oncology (2023)

e20509 Background: Risk stratification for patients with non-small cell lung cancer (NSCLC) has historically been evaluated using TNM staging, but there are several other pathological features that have been identified as poor prognostic factors such as lymphovascular invasion, visceral pleural invasion, micropapillary pattern, and more recently, spread through airspaces. There is considerable data linking lymphovascular invasion to poor prognosis and emerging data suggesting spread through airspaces as a poor prognostic factor, but there is limited data comparing the prognostic power of lymphovascular invasion to spread through airspaces. This study aims to distinguish lymphovascular invasion from spread through airspaces as a prognostic factor and to further investigate the correlation of these to other pathologic markers. Methods: Retrospective review of the histopathologic diagnosis, recurrence, and survival status of 720 patients who underwent surgical excision of NSCLC between 2015 and 2019 was conducted. The relationships between pathological factors and prognosis were evaluated with chi square tests and a binary logistic regression was performed. Patients with stage V disease and those treated with neoadjuvant chemotherapy were excluded. Prognosis was assessed using documentation of recurrence of the primary tumor and survival status at the time of chart review. Results: Of the 720 patients, 61 patients had lymphovascular invasion (7.2%) and 56 patients had spread through airspaces (7.1%). Lymphovascular invasion was associated with a statistically significant increase in recurrence and patient mortality across stages I-III collectively, and stage I disease independently. Spread through airspaces was not associated with a statistically significant increase in recurrence or patient mortality in stage I-III or in stage I disease independently. Lymphovascular invasion was also significantly correlated to a greater number of nodal metastases, higher frequency of a micropapillary component, higher frequency of visceral pleural invasion, and increased tumor size. Spread through airspaces was significantly correlated to each of the same pathological risk factors except increased frequency of visceral pleural invasion and increased tumor size. Conclusions: The presence of lymphovascular invasion increases risk of recurrence and mortality and is associated with all of the additional pathological risk factors measured making it more relevant pathologically and prognostically than spread through airspaces.
Massively multiplex blocker displacement amplification (BDA) for the detection of measurable residual disease in acute myeloid leukemia.
Authors: Wenjun Li, Shaoheng Liang, Hannah Roberts, Long Dao, Alessandro Pinto, David Zhang, Yalei Wu
Journal: Journal of Clinical Oncology (2023)

e19045 Background: Next-generation sequencing (NGS) technologies, used to accomplish high throughput characterization of DNA, have an inherent error rate of between 0.1-1%. However, many important DNA sequences possess variant allele frequencies (VAFs) below this rate, potentially precluding their detection and identification by NGS. The previously published blocker displacement amplification (BDA) research technology has enabled selective amplification of sequences with variants, facilitating detection by NGS of these sequences with low VAFs at low read depths. Methods: Here we present the massively multiplex BDA library preparation method for the NGS-based detection of low VAF sequences. By optimizing our previously published Simulated Annealing Design using Dimer Likelihood Estimation (SADDLE) algorithm, we designed a 4 tube assay, comprising up to ~2400 amplicons in each tube, and ~8300 total amplicons. Tube 1 was designed with the highest likelihood of on-target amplification and the lowest likelihood of dimerization or non-specific amplification. While Tube 1 targeted ~1000 regions covering the most-frequently observed mutations in current public databases of patients with acute myeloid leukemia (AML) across more than 200 genes, Tubes 2-4 were designed for enrichment of the full coding sequence of 63 genes. To highlight the performances of SADDLE, coverage uniformity, primer dimerization, and non-specific amplification of tube 1 were compared to those of a naively designed tube. The panel was further tested with contrived and reference samples to demonstrate its analytical performance. Results: The SADDLE algorithm design decreased the first pass amplicon dropout rate more than 10-fold, from 30% to ~2%, and further improved the overall on-target rate compared to the naively designed panel. Through SADDLE, we were able to achieve an 80% median coverage of 63 genes. The resulting panel has a bulk limit of detection (LoD) of below 0.1% VAF. Conclusions: Massively multiplex BDA enabled the NGS characterization of DNA targets with VAFs suitable for detection of AML measurable residual disease (MRD). This technology represents a 100-fold increase in current plexity for the detection of low VAF alleles over our previously published multiplex BDA technology, demonstrating the ability to perform high throughput sequencing of rare mutations.
Pediatric cancer registry in Turkey 2002-2022: 21 years of achievement (TPOG &amp; TPHD).
Authors: M. Tezer Kutluk, Akif Yeşilipek
Journal: Journal of Clinical Oncology (2023)

e22004 Background: Each year 413.000 new pediatric cancer cases are expected in children and adolescents aged 0-14 globally. The access to care is still a barrier to improve the survival rates in low and middle income countries (LMICs). Pediatric cancer registry is the essential element of pediatric cancer control. Here, we present the results of the 21 years of the pediatric cancer registry from Turkey. Methods: Turkish Pediatric Oncology Group and Turkish Pediatric Hematology Association has established the pediatric cancer registry in 2002. The childhood cancer cases registered between 2002-2022 was included in this analysis. International Childhood Cancer Classification System was used for the classification. Essential demographic findings, ICD-O-3 morphology and topography codes were recorded for each case. Results: During the 21 years from 2002 to 2022, 46067 cases were registered. For all cases, median age was 6.5 year (0-19; M/F 25079/20176, 6 hermaphrodite, 6 unknown). Age distribution was 0-4 yrs, 41.5%; 5-9 yrs, 24.7%; 10-14 yrs, 23.0%; 15-19 yrs, 10.7%) The distribution of the tumor types were [number of cases, percentage of total, median age yrs, M/F]: Leukemia (13190, 28.6%, 5.6, 7640/5550); Lymphoma &amp; other RES tumors (8194, 17.8%, 9.1, 5435/2756, 1 hermaphrodite &amp; 2 unknown); CNS [brain &amp; spinal] (6606, 14.3%, 6.8, 3670/2935, 1 unkown); Symphatetic system (3411, 7.4%, 2.3, 1755/1656); Retinoblastoma (1386, 3.0%, 1.5, 726/660); Renal (2095, 4.5%, 3.1, 1032/1061, 1 hermaphrodite &amp; 1 unknown); Liver (681, 1.5%, 2.1, 400/281); Malignant bone (2809, 6.1%, 12.5, 1569/1240); Soft tissue sarcomas (3209, 7.0%, 7.3, 1810/1399); Germ cell (2663, 5.8%, 8.6, 957/1700, 4 hermaphrodite, 2 unknown); Carcinoma &amp; other malignant epithelial (1494, 3.2%, 13.0, 721/773); Other/non-specific malignant (329, 0.7%, 7.4, 164/165). Five year survival rate was found as 70.8% Conclusions: This is a successful example of a pediatric cancer registry from a middle income country covering the period of more than 20 years. The survival rates for children and adolescents have been improved to 70% which is comparable for middle income countries and reflects the level of the pediatric cancer care in Turkey. It became a valuable source for stakeholders in national and international level.
Impact of first-line immunotherapy on survival and intracranial outcomes from a real-world cohort of patients with non-small cell lung cancer with brain metastases at diagnosis.
Authors: Benoît Nigen, Laurent Mathiot, Thomas Goronflot, Guillaume Herbreteau, Christine Sagan, Judith Raimbourg, Jaafar Bennouna, Francois Thillays, Elvire Pons-Tostivint
Journal: Journal of Clinical Oncology (2023)

9058 Background: Although brain metastases (BM) at diagnosis are common in non-squamous NSCLC patients (ns-NSCLC), they have been mostly excluded from randomized trials. The aim of this retrospective study was to evaluate real-word outcomes of frontline immune checkpoint inhibitor (ICI) in these patients. Methods: We conducted a retrospective study to assess the intracranial and overall efficacy of first-line ICI-based therapy compared to chemotherapy (CT) in ns-NSCLC patients diagnosed with BM, showing no targetable alterations. Patients were divided according to systemic therapy: CT, ICI, or CT-ICI respectively. Primary endpoint was overall survival (OS), compared using Kaplan-Meier and Cox methodology. Secondary endpoint was intracranial progression free survival (icPFS). Results: Between 01-2018 and 05-2021, 118 newly diagnosed ns-NSCLC patients with BM were included (52 CT, 38 ICI and 28 CT-ICI). Median follow-up was 30.0 months [95% CI: 25.9-36.0]. Intracranial radiotherapy was delivered for 75.0%, 68.4% and 67.9% of patients for CT, ICI and CT-ICI groups (p = 0.805) respectively. OS rates at 24 months were respectively 25.3% (95% CI: 15.7-40.9), 44.6% (95% CI: 30.8-64.7) and 50.5% (95% CI: 34.3-74.4) in CT, ICI and CT-ICI groups (p = 0.048). Twelve-month icPFS was respectively 17.0% (95% CI: 9-32), 47% (95% CI: 33-66) and 45% (95% CI: 30-69) in CT, ICI and CT-ICI groups . After adjustment, ICI and CT-ICI were associated with a better OS compared to CT (HR = 0.46, 95%CI: 0.23-0.89, p = 0.021 and HR = 0.52, 95%CI: 0.27-1.01, p = 0.054 respectively). ICI and CT-ICI were associated with a significant reduction in the risk of intracranial progression by 54% (HR = 0.46, 95%CI: 0.25–0.84, p = 0.0123) and 59% (HR = 0.41, 95%CI: 0.23–0.77, p = 0.0050) compared to CT. Stereotactic radiosurgery was associated with an increased icPFS compared to systemic therapy alone (HR = 0.51, 95% CI: 0.29 – 0.92, p = 0.0247), whereas whole-brain was not (p = 0.096). Conclusions: Real-life ns-NSCLC patients with BM at diagnosis treated frontline with ICI presented OS and icPFS benefit compared to CT alone. A prospective assessment of the ideal type and sequence of systemic and local therapy should be conducted.